1. Field of Invention
This invention relates to a novel process for preparation of racemic Nebivolol, its enantiomeric compounds and to novel compounds made by the process.
2. Description of Related Art
Nebivolol (see FIG. 1A, showing d-Nebivolol, chemical name: [2R*[R*[R*(S*)]]]-α,α′-[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] or alternatively [2R*[R*[R*(S*)]]]-α,α′-[iminobis(methylene)]bis[6-fluoro-chroman-2-methanol] and FIG. 1B showing a racemic Nebivolol, which is a mixture of l- and d- Nebivolol) is known as an adrenergic beta-antagonist, an antihypertensive agent, a platelet aggregation inhibitor and a vasodilating agent.
Nebivolol is administered as tablets (e.g., a dosage of 5.45 mg Nebivolol hydrochloride is equivalent to 5 mg Nebivolol) which contain Nebivolol as a racemic mixture of enantiomers SRRR-Nebivolol (dextro d-Nebivolol) and RSSS-Nebivolol (levo l-Nebivolol).
Nebivolol contains four asymmetric centers, and therefore 16 stereoisomers are theoretically possible. However, because of the particular constitution of the structures and configurations of the stereoisomers (e.g., axial symmetry), only 10 stereoisomers (6 diastereomers: 4 dl forms and 2 meso forms) can be formed (Table 1).
A non-stereoselective preparation of these stereoisomers is generally described in U.S. Pat. No. 4,654,362 to Van Lommen et al. (Janssen Pharmaceutica N. V.) (and its counter-part EP 0145067). A stereoselective synthesis of the isomer [2R, αS, 2′S, α′S]-α,α′-[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] has been described in U.S. Pat. No. 6,545,040 (Janssen Pharmaceutica N. V.) (and its counter-part EP 0334429).
A PCT patent application publication WO 2004/041805 (Egis Gyogyszergyar R T.) describes a new process for the preparation of racemic [2S[2R*[R[R*]]]] and [2R[2S*[S[S*]]]]-(±)α,α′-[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] and its pure [2S[2R*[R[R*]]]]-, and [2R[2S*[S[S*]]]] enantiomers.
Alternative and enantioselective syntheses of d-Nebivolol were described in J. Am. Chem. Soc. 1998, 120, 8340-8347 and Tetrahedron 56, 2000, 6339-6344.
TABLE 1Stereoisomers of Nebivolol a general formula for Nebivolol isomersR2 =R1 =SRRS stereoisomer 1SRRR stereoisomer 2 d-NebivololSRSR stereoisomer 3 meso form 1SRSS stereoisomer 4 RRRS stereoisomer 2 d-NebivololRRRR stereoisomer 5RRSR stereoisomer 6RRSS stereoisomer 7 meso form 2 RSRS stereoisomer 3 meso form 1RSRR stereoisomer 6RSSR stereoisomer 8RSSR stereoisomer 9 l-Nebivolol SSRS stereoisomer 4SSRR stereoisomer 7 meso form 2SSSR stereoisomer 9 l-NebivololSSSS stereoisomer 10
Methods of preparation of Nebivolol as described in the above mentioned references are summarized below.
a. U.S. Pat. No. 4,654,362 (and its counter part EP 0145067 U.S) (Janssen Pharmaceutica N. V.)
The synthetic route for the non-stereoselective preparation of Nebivolol is described, starting from 6-fluoro-4-oxo-4H-1-benzopyran-2-carboxylic acid a1 (Scheme 1a):

For the preparation of Nebivolol according to the Scheme 1a, U.S. Pat. No. 4,654,362 and its counter-part EP 0145067 contain detailed examples for the synthesis of components a1, a2, a3, a4 and a8 only. All other examples are analogue procedures that describe the preparation of related derivatives (e.g., derivatives without the aromatic fluoro substituent). The general strategy for the preparation of Nebivolol or its corresponding derivatives is based on the synthesis of the 2-oxiranyl-chromans (a6 and a7) as key intermediates for the final coupling steps. Because they possess two asymmetric carbon atoms, these compounds may be formed from the racemic aldehydes a5 as two diastereomeric racemates (“an A form” a7=RS/SR and “a B form” a6=SS/RR) which may be separated by chromatography. This reference does not provide descriptions of a workup procedure, crystallization and purification or separation of stereoisomers, yields etc. for the desired intermediates.
The racemates a6 or a7 can be transformed by reacting with benzylamine to the corresponding benzylated aminoalkohols a8 and a9. A benzyl protected Nebivolol AB mixture a10 may be prepared by reacting of the racemate a8 (RS/SR) with the epoxide racemate a6 (RR/SS) or by reacting of racemate a9 (RR/SS) with the epoxide racemate a7 (RS/SR). The protecting group may be removed in the final step by catalytic hydrogenation to give a Nebivolol AB mixture a11.
Scheme 1b shows further methods for the synthesis of the analogous 2-chromanyl-aldehydes (a14) and 2-oxiranyl-chromanes (a16) as key intermediates for the synthesis of Nebivolol derivatives having different substituents at the aromatic moiety.

The aldehyde a14 can be obtained by low temperature reduction of the imidazolide of a12 or by the same reduction of the ester a13. The aldehyde a14 is then converted into the 2-oxiranyl-chromans a16 by reaction with sodium hydride and trimethyl sulfoxonium iodide in dimethyl sulfoxide in an analogous reaction as described above. Another possibility for the synthesis of 2-oxiranyl-chromans a16 is the oxidation of 2-vinylchroman a15 with 3-chlorobenzenecarboperoxide (the source of 2-vinylchroman a15 is not described in these patents but according to EP 0334429 (see also below), compound a14 can be converted into compound a15 by a Wittig reaction).
Scheme 1c demonstrates that diastereomeric mixtures consisting of desired and undesired diastereomers (i.e., RSSS/SRRR and RSRR/SRSS) can be produced by the method shown in Scheme 1a.

The strategy described in U.S. Pat. No. 4,654,362 and its counter-part EP 0145067 has the following disadvantages:
1. The synthesis of the aldehydes a6 and a14 requires very low temperatures and therefore requires special equipment, which makes the process more complicated and expensive;
2. The aldehyde a5 is very unstable as stated in a PCT publication WO 2004/041805;
3. The synthesis of a6/a7 from a5 may be hazardous because it is known that the use of sodium hydride in solvents like DMSO, DMF, DMA and DMI can cause an exotherm and therefore, cause a runaway reaction (see UK Chemical Reaction Hazards Forum: “Sodium 15 Hydride/DMF process stopped”);
4. Compounds a6 and a7 have been characterized as oily substances (see PCT publication WO 2004/041805). Since the preparation according to the described procedure is likely to form a diastereomeric mixture of a6 and a7, chromatographic purification may be required, which is not commercially viable;
5. Compounds a10 and a11 may be prepared by reaction of the racemic intermediate a8 (“isomer A”) with the racemate a6 (“isomer B”) or alternatively by reaction of the racemic intermediate a9 (“isomer B”) with the racemate a7 (“isomer A”) followed by deprotection. U.S. Pat. No. 4,654,362 and its counter-part EP 0145067 do not provide an explicit description as to whether the compounds a10 and a11 (characterized only as being the “AB” isomeric form) are single isomers or a mixture of isomers. No teaching for separation of such mixtures has been provided. It is obvious that such procedures may form diastereomeric mixtures consisting of the desired RSSS/SRRR diastereomer and the undesired RSRR/SRSS diastereomer (Scheme 1c; also compare Table 1 demonstrating combination of the different fragments to give all possible diastereomers). Moreover, it is known in prior art (see WO 2004/041805) that racemic Nebivolol prepared according to the process disclosed in U.S. Pat. No. 4,654,362 (and its counter-part EP 0145067) (Schemes 1a and 1c) and obtained as the diastereomeric racemate having the SRSS/RSRR configuration could not be successfully separated by fractional crystallization; and
6. The loss of expensive material via the formation of undesired Nebivolol isomers, especially during late process steps.
b. EP Patent Application Publication EP 0334429 and U.S. Pat. No. 6,545,040 to Xhonneux et al. (Janssen Pharmaceutica N. V.)
Similar strategy for the synthesis of Nebivolol is described in EP 0334429 and U.S. Pat. No. 6,545,040 but with the difference that l-Nebivolol is prepared by an enantioselective synthesis using the enantiopure fragments b6 and b11 (Scheme 2) as key intermediates.

For this procedure, it was necessary to separate the racemic 6-fluoro-chroman-2-yl-carboxylic acid b2 by formation of a diastereomeric amide b3 with (+)-dehydroabietylamine followed by fractional crystallization of the diastereomers and hydrolysis of the amides. The next steps for the synthesis of the fragments b6 and b11 were done in convergent pathways using the (S)-form and (R)-form of the 6-fluoro-chroman-2-yl-carboxylic acids b4 and b8. The (S)-6-fluoro-chroman-2-yl-carboxylic acid b4 was first converted to the aldehyde b5 according to the procedure, already mentioned in scheme 1b. The epoxide b6 could be then obtained by reacting of b5 with sodium hydride and trimethyl sulfoxonium iodide in dimethyl sulfoxide. On the second pathway the (R)-6-fluoro-chroman-2-yl-carboxylic acid b8 was first esterified to b9. Epoxide b10 was synthesized in a one-pot procedure by reduction of b9 to the corresponding aldehyde followed by reaction with sodium hydride and trimethyl sulfoxonium iodide in dimethyl sulfoxide. The epoxide ring of b10 was opened by substitution with benzylamine to give the second key fragment b11, which was then reacted with the epoxide b6 to obtain benzyl-protected l-Nebivolol b12. Final deprotection by catalytical hydrogenation of b12 gave 1-Nebivolol.
The strategy described in EP 0334429 and U.S. Pat. No. 6,545,040 has the following disadvantages:
1. The steps of preparing compounds b5 from b4 and b10 from b9 require very low temperatures for the diisobutylaluminum hydride (DIBAH) reduction, making the process more complicated and expensive due to the need for special refrigerating equipment;
2. The steps of preparing compounds b6 from b5 and b10 from b9 may have safety hazards because it is known that the use of sodium hydride-in solvents like DMSO, DMF, DMA and DMI can lead to an exotherm and could cause a runaway reaction (see UK Chemical Reaction Hazards Forum: “Sodium Hydride/DMF process stopped”);
3. Compounds b5, b6, b9 and b10 are oily substances and therefore difficult to purify; in the likely case that compounds b6 and b10 are contaminated with undesired diastereomers, separation by column chromatography may be required, which is not a commercially viable procedure;
4. The low yields, especially those of steps of preparing compounds b2-b3-b4, b2-b7-b8 and b5-b6, b9-b10, result in a very low overall yield (≦0.5%) for the synthesis of l-Nebivolol making this procedure uneconomical;
5. Since only l-Nebivolol is prepared and a racemic mixture is required for preparation of Nebivolol, additional steps are necessary to synthesize the corresponding d-form (i.e., d-Nebivolol); and
6. Upon reacting the intermediate b2, diastereomers b3 and b7 were formed which then had to be separated and treated separately to yield b6 and b11, later combined to yield b12, thus requiring multiple additional steps in the process.
c. PCT Patent Application Publication WO 2004/041805 to Trinka et al., (EGIS GYOGYSZERGYAR RT)
WO 2004/041805 describes the enantioselective synthesis of d- and l-Nebivolol (see Schemes 3a-c).

The strategy of this route is based on the synthesis and separation of isopropylidene protected (1′,2′-dihydroxy-ethyl)-6-fluoro-chroman-4-one isomers c11, c12, c13, c14 (Scheme 3a). These compounds were synthesized by starting with the Friedel-Crafts acylation of 4-fluoroanisole c1 using chloroacetyl chloride to give the chloroacetyl compound c2, which was further transformed with triphenylphosphine followed by treatment with a weak base to form the stable phosphanylidene compound c4. The compound c4 was then reacted separately with protected glycerinealdehydes c6 (obtained from vitamin C) to give c11 and c12 or with c8 (obtained from D-mannitol) to give c13 and c14 after the cycling.
Each of these isomers was further transformed in four pathways and in the same manner (Schemes 3b and 3c), whereby according to pathways 1 and 2, l-Nebivolol was prepared using c11 and c12 as starting compounds (Scheme 3b).
The enantiomeric d-Nebivolol was prepared in the analogous fashion, wherein the starting compounds were the S,R-isomer c13 and R,R-isomer c14 of isopropylidene protected (1′,2′-dihydroxy-ethyl)-6-fluoro-chroman-4-one (pathways 3 and 4, Scheme 3c).
The typical reaction sequence for each pathway started with the deprotection of c11 (pathway 1, Scheme 3b), c12 (pathway 2, Scheme 3b), c13 (pathway 3, Scheme 3c), c14 (pathway 4, Scheme 3c) to obtain the respective diols c15, c19, c25, c29. Selective tosylation of the primary alcohol group gave the compounds c16, c20, c26, c30 which could be transformed to the epoxides c17, c21, c27, c31 by treatment with a base. After the conversion of these epoxides with benzylamine to c18, c22, c28, c32 and substitution with the desired epoxides (c18+c21, c22+c17, c28+c31, c32+c27), the benzyl protected diketo compounds c23 and c33 were formed. Deprotection and reduction of the carbonyl groups could be carried out in a one pot reaction by catalytic hydrogenation to give either 1-Nebivolol or d-Nebivolol.
Racemic Nebivolol was obtained by preparing a 1:1 mixture of the intermediates c23 and c33 before performing the last hydrogenation step (yield 52%).


The strategy described in WO 2004/041805 has the following disadvantages:
1. Although the strategy is based on the use of all stereoisomers to synthesize either l-Nebivolol or d-Nebivolol, the main disadvantage is that up to 30 steps are necessary to get the racemic mixture by using all intermediates, which makes the production protracted and uneconomic; and
2. The steps of making compounds c23 from c18, c23 from c22, c33 from c28 and c33 from c32 are carried out without the use of a solvent at 145° C. (presumably after melting of the reactant). Such a procedure is not feasible on large scale.
d. Johannes et al., J Am. Chem. Soc. (1998), 120, 8340-8347
The Johannes et al. article describes an enantioselective preparation of d-Nebivolol (Scheme 4).

The strategy is based on the syntheses of the chiral chroman fragments d12 (R, R-configuration) and d21 (S, S-configuration) as key intermediates in convergent pathways which are finally coupled to give, after deprotection, d-Nebivolol. The essential step for the syntheses of these chiral chromans is the Zr-catalyzed kinetic resolution of the racemic intermediates d7 and d16.
According to the first pathway, the starting material for the preparation of chromane fragment d12 was the salicylic aldehyde d3, which was synthesized either by formylation of compound d1 or by reaction of the lithiated compound d2 at −60° C. with DMF. The allylic cycloheptene epoxide which could be obtained by epoxidation of cycloheptadiene was then reacted with aldehyde d4 to give the racemic compound d7 by a regioselective and stereoselective nucleophilic opening of epoxide d8. Protection of the hydroxyl group of d7 using TBSOT followed by treatment with 5 equiv EtMgCl and 10 mol % (R)-(EBTHI)Zr-binol delivered d8 in 44% yield and >98% ee. The Mo-catalyzed metathesis reaction under an ethylene atmosphere, followed by Wacker oxidation ofthe terminal double bond and subsequent catalytic hydrogenation, gave d10 in 83% overall yield. To synthesize d11 from d10, a photochemical Norrish type II cleavage was necessary. The following three-step sequence of ozonolytic cleavage, Mitsunobu reaction using tributylphosphine and phthalide followed by hydrazinolysis to remove the phthalimidyl group gave intermediate d12. The second pathway started with the synthesis of cis configured racemate d16, which was then resolved in the presence of the Zirconium catalyst (S)-(EBTHI)Zr-biphenol. The compound d17 was converted into compound d18 by Mo-catalyzed metathesis reaction. Wacker oxidation of the terminal double bond and subsequent catalytic hydrogenation delivered intermediate d19, which was further converted by a photochemical Norrish type II cleavage and ozonolysis into the aldehyde d21. D-Nebivolol was then obtained by reductive amination of compounds d12 and d21 followed by removal of the silyl ether protection groups.
The strategy described in the Johannes et al. article has the following disadvantages:
1. Preparation of aldehyde d3 occurs either in a low yield by formylation of d1 using chloroform in the presence of a base or requires low temperature by lithiation and formylation of compound d2. Furthermore, handling of n-Buli during a scale-up process requires special precautions;
2. The steps of preparing compounds d8 from d7 and d16 and d17 from d13/d14 also require low temperature (−78° C.) for the silylation. Furthermore, a difficult resolution step using a special commercially unavailable Zr-catalyst is necessary;
3. The steps of preparing compounds d10 to d11 and d19 to d20 require special equipment for the photochemical reaction (Norrish type 2 cleavage);
4. The step of preparing compound d12 from d11 requires low temperature (−78° C.) and special equipment for the ozonolysis; and
5. 16-20 steps are necessary for the synthesis of one Nebivolol enantiomer (d-form), but the racemic mixture is required; thus, additional steps are necessary to synthesize the corresponding 1-form (i.e., l-Nebivolol).
e. Chandrasekhar et al., Tetrahedron (2000), 56, 6339-6344
The Chandrasekhar et al. article describes another procedure for the enantioselective synthesis of d-Nebivolol (see Scheme 5).

The basis for the enantioselective strategy is the asymmetric one-pot Sharpless epoxidation of allyl alcohol e7 using (−)-DET and (+)-DET to provide both enantiomeric diols e8 and e12 after a cyclization step.
The starting compound was 4-fluoro-phenol e1, which was first converted into the allylether e2. Claisen rearrangement at 210° C. followed by protection of the phenol group (e3) with TBDMS-Cl gave the intermediate e4. The primary alcohol e5 was obtained by hydroboration and subsequent oxidative treatment using H2O2. This product was converted into the α, β-unsaturated ester e6 by one pot oxidation with Dess-Martin periodane and Wittig olefination. Afterwards, the compound e6 was reduced with DIBAL-H to the allyl alcohol e7. At this stage, the route was divided into two pathways each starting with the asymmetric Sharpless epoxidation and cyclization in one pot. On the first pathway, the diol e8 could be obtained in 65% yield by using (−)-DET. Selective tosylation of the primary alcohol e8 and substitution of e9 with azide followed by catalytical reduction of e10 gave the aminoalcohol e11. On the second pathway, the diol e12 was synthesized in an almost similar manner as diol e8 but with the exception that (+)-DET was used for the Sharples epoxidation to give the corresponding enantiomeric compound. Inversion at the C2 carbon under Mitsunobu conditions with p-Nitrobenzoic acid gave the di-PNB protected compound e13. After removal of the protection groups, the diastereomeric diol e14 could be obtained. Selective tosylation of e14 and treatment of resulting e15 with a base yielded epoxide e16. The synthesis of d-Nebivolol hydrochloride could be completed by coupling of aminoalcohol e11 with epoxide e16 followed by transformation to the hydrochloride salt.
The strategy described in the Chandrasekhar et al. article has the following disadvantages:
1. Step of making compound e3 from e2 requires high temperature for the Claisen rearrangement, which is not practicable a in scale-up procedure;
2. Up to 16 steps are necessary to synthesize only one Nebivolol enantiomer, but the racemic mixture is required;
3. The last coupling step yields d-Nebivolol in a low yield (20%);
4. The Asymmetric Sharpless epoxidation is known to give non-enantiopure products. Therefore contaminations with other stereoisomers are likely. As already mentioned in WO 2004/041805, the described method for the measurement of the optical purity is not sufficient to determine such possible contaminations.
5. Almost all intermediates were purified by column chromatography because most intermediates are oily compounds.
In summary, multiple steps (>13 steps), the low yield, the usage of unusual catalyst, reaction conditions, special equipment and column chromatography for purification of the predominantly oily intermediates makes the available strategies and most of the steps too laborious and economically unsuitable for a commercial process.
Despite the above described efforts, there is a need for a new, efficient and commercially feasible process for the preparation of racemic Nebivolol having an improved overall yield.
All references cited herein are incorporated herein by reference in their entireties.